EnosiTherapeutics Logo Draft 10 14 2022

Technology

Platform

Ligand Traps:
Receptor extracellular domain (ECD):Fc fusion proteins (‘Traps’) are useful as therapeutics. Examples are Enbrel/etanercept (TNF) for autoimmune diseases, aflibercept/Eylea (VEGF) as an anti-angiogenic agent in eye diseases, Orencia/abatacept (CTLA-4-Fc) for autoimmune diseases, and most recently, luspatercept, a transforming growth factor (TGF)-Beta ligand trap for the treatment of myelodysplastic syndrome.

Ligand Traps

Ligand traps deplete excess ligands/growth factors/cytokines and leave some behind to support normal cell function.

Many receptors can bind multiple ligands simultaneously, commonly to a single site on the cognate receptor. The prototypical examples are members of the human EGFR (HER) family. Other receptors with multiple ligand binding include Tie-2, the FGFR family, TNFR1/TNFR2, and VEGFR1. Enosi has learned how to selectively modify Traps such that they will have enhanced binding for selected ligands.

Enosi has developed an AI-driven (in silico) method capable of optimizing affinity of ligands to their binding site(s) to receptor:Fc fusion proteins capable of making their ligand-trapping comparable to the cell membrane-associated receptors, and therefore better ligand traps than those existing today. Enosi’s TRAP technology can be applied to soluble or cell-associated targets (or both) in a monospecific or multispecific format. TRAPS avoid the common toxicity associated with receptor-targeted antibody therapeutics which occurs when the receptor is not overexpressed on the target tissue. This occurs via ADCC or because of inappropriate shut-down of receptor function in normal tissues. This hurdle has been particularly encountered for all anti-EGFR antibodies and limits their utility.

Single-Armed Antibodies: Enosi is developing single-armed antibodies in cases where bivalent antibody-mediated receptor clustering is not wanted because of potential activation. Whereas transient activation of receptor function is commonplace with antagonist antibodies, like trastuzumab/Herceptin, in the case of TNFR1 this may be disastrous if the cytokine cascade/storm is activated. Thus, a TNFR1 molecule must be designed that does not trigger clustering and is not a significant agaonist.

Single Armed Antibodies

Product Pipeline

1. The EN-2000 Program (Targeting growth factors that activate the EGFR family)

The receptor tyrosine kinases (RTKs) in the Human Epidermal Growth Factor Receptor (HER) family play a key role in important cellular processes and signal transduction mediated by the binding or dissociation of their ligands. Dysregulation of the RTKs has been shown to be associated with multiple types of cancers and other diseases such as autoimmune and inflammatory diseases, chronic kidney disease, and liver pathologies. The HER family is composed of four RTK members: EGFR (HER1), HER2, HER3 and HER4. Among these, EGFR and HER4 are fully functional in terms of ligand binding and kinase activity, while HER2 is still an orphan receptor and HER3 is deficient in tyrosine kinase activity and relies on the kinase activity of its heterodimerization partners and its phosphatidyl inositol p85 regulatory subunit binding sites for signaling. There are at least 11 distinct ligands (plus spice variants) that activate the HER family, and 9 of these are targeted by Enosi’s Pan-HER trap. The Pan-HER trap is designed to protect the HER4/Neuregulin 3,4 interactions which are important for cardiomyocytes and other important physiologies.

Enosi ligand trap does not deplete NRG 3 and 4

There are many programs targeting the EGFR family for disease treatment. Kinase inhibitors and antibodies are the most common. However, current therapies face many challenges. For example, small molecule kinase inhibitors lack the specificity enjoyed by biologics. This leads to toxicity at doses required to achieve maximum efficacy. The therapeutic effect of antibodies is limited in some cases because their targets are not overexpressed, making it impossible to discriminate between normal and diseased cell types. The best known example of this situation is Erbitux/cetuximab, or combinations of antibodies that contain an anti-EGFR antibody. Enosi’s technology offers a new approach to treatment of malignancies and other diseases associated with the HER family because it employs the specificity of a biologic coupled with targeting disease-associated overexpression of growth factors.

Enosi’s lead molecule is EN-2642, a bispecific composed of optimized EGFR-Fc and HER3-Fc. Both Fc components are engineered for serum half-life extension. EN-2642 captures excess growth factors which tumor cells (but not normal cells) depend for proliferation, thereby starving diseased cells without impacting normal cell function, similarly to other ligand traps, eg., aflibercept (VEGF Trap), luspatercept (TGF-beta trap).

heterodimer

Image of the EGFR-Fc:HER3-Fc heterodimer. This molecule is EN-2242. Enosi is moving forward with a mixture of this heterodimer combined with the EGFR-Fc and HER3-Fc homodimers (EN-2642), co-expressed in CHO cells, based upon in vitro data showing superiority of the mixture over the heterodimer alone (new IP).

In vivo studies have shown that the parent (non-optimized) version of EN-2642 is active in rheumatoid arthritis (RA) mouse models and in human xenograft tumor models. Data below shown that EN-2242 is active on non-HER2 overexpressing lung cancer cells, which cetuximab, trastuzumab, and pertuzumab have little activity.
inhibition of H441 proliferation

2. The EN-1000 Program (Specifically targeting TNFR-1)

Autoimmune and inflammatory diseases are a major therapeutic indication, as tens of millions of people in the U.S. suffer from them. TNF is a key protein implicated in these ailments, and therapeutics targeting TNF generate over $40B USD of sales each year. These drugs have been used to treat rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, and ankylosing spondylitis. Despite their clinical success, however, these anti-TNF therapeutics have limitations. A significant portion of patients do not respond to the treatment and, for those who do respond, nearly half stop responding during therapy. In addition, anti-TNF drugs can lead to severe side-effects, including infections, reactivation of latent tuberculosis, increased susceptibility for development of additional autoimmune diseases, demyelination diseases, cardiovascular disease and an increased risk to develop lymphomas. Inhibition of the JAK kinase pathway, another key pathway implicated in autoimmune and inflammatory diseases, has also resulted in similar issues. New approaches are needed to overcome these difficulties.

There are two types of TNF receptors. Interaction between TNF and TNFR-1 produces proinflammatory effects, while that between TNF and TNFR-2 produces anti-inflammatory effects. The current TNF blockers affect both TNFR-1 and TNFR-2. This non-specificity leads to adverse effects, preventing these conventional therapeutics from being used for treatment of many chronic diseases, including acute Covid, Alzheimer’s and many others.
Enosi is addressing this challenge by focusing on direct inhibition of the pro-inflammatory TNFR-1 while preserving the function of the anti-inflammatory TNFR-2. Intial studies with candidate precursor molecules showed that that these tool molecules are effective at blocking TNF-induced production of cytokine release syndrome (CRS) effector molecules. Enosi has designed two single-armed antibodies, EN-1206-Fc and EN-1208-Fc which target TNFR-1, specifically for the purpose of avoiding formation of higher order TNFR1 multimers.

anti TNFR1 Multimers
Group 3 Copy 2

James N. Woody

Executive Chairman

  • Jim brings more than 25 years of pharmaceutical research and management experience to Enosi.
  • In addition to his duties as a consultant to LVP, where he served as a General Partner for 14 years, Jim is currently Chairman of Viracta Therapeutics, a company focusing on unique therapies for virally induced cancers.  
  • He was the founding CEO of OncoMed Pharmaceuticals, a cancer therapeutic antibody company. He was the Board member for both ForteBio, and Protein Simple, both successfully acquired. Jim was formerly President and GM of Roche Bioscience (former Syntex) in Palo Alto, CA. 
  • Previously, Jim served as Chief Scientific Officer and Senior Vice President of R&D for Centocor. While at Centocor, Jim’s team developed the blockbuster drug Remicade. 
  • Jim served as a Navy Medical Officer, and was Head of the Navy Transplant Research Program. With his colleagues and with both Navy and Congressional support, founded the National Marrow Donor Program. 
  • He was promoted to Commanding Officer and Director, US Naval Medical Research and Development Command in Bethesda Maryland. He was responsible for the surveillance, detection and therapy for all Biologic Warfare Agents and Infectious Diseases in the first Gulf War and was awarded the Marine Corps/US Navy Legion of Merit for his service. 
  • Jim served as Chairman of the Silicon Valley Leadership Group representing over 120 Silicon Valley Companies, is a board member of the Lucile Packard Children’s Hospital (Stanford).
  • Jim holds an M.D. from Loma Linda University, trained in Pediatric Immunology at Duke University and Children’s Hospital in Boston (Harvard), and holds a Ph.D. in Immunology from the University of London, England. He was Professor of Pediatrics and Microbiology at Georgetown University School of Medicine 1982-1996. He has authored or co-authored over 140 publications.
Group 3 Copy

H. Michael Shepard, Ph.D.

CEO & Co-founder

  • Dr. H. Michael Shepard is a global, leading authority on cancer research and therapeutics.
  • Best known for his invention of “Herceptin”/Trastuzumab, which has remained one of the most profitable platforms for Roche (>$7B USD).
  • Dr. Shepard is a highly-experienced and respected leader with many successful ventures in this field – working at Genentech (sold to Roche – $46.8 B USD), Canji, Inc. (bought by Scheirng-Plough) and Halozyme (now valued at $2.6B USD).
  • Widely acknowledged biomarker pioneer and recognized worldwide, Dr. Shepard has received the 2019 Albert Lasker Award and the Warren Alpert Prize, among many other professional accolades.

Enosi Team SirMarc Lasker Circle

Sir Marc Feldmann, M.D. Ph.D.

Director & Co-founder

  • Sir Marc Feldmann is a preeminent immunologist, and an Emeritus Professor at the University of Oxford.
  • With Sir Ravinder Maini, identified TNF as a target. Trials of Infliximab (Remicade) they led were successful, and prompted J&J’s $4.9B USD acquisition of Centocor.
  • Anti-TNF sales > $50B USD globally.
  • Professor Sir Marc Feldmann is a Fellow of the Royal Society , of Australian Academy and a Foreign Member of the US National Academy of Sciences; he was knighted in 2010 and received the Australian equivalent.
  • He has received many accolades including the Albert Lasker Award, the Crafoord Prize, the Canada Gairdner Award, the Paul Janssen Award, the Ernst Schering Award.